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Decarboxylative intramolecular arene alkylation using N(acyloxy)phthalimides, an organic photocatalyst, and visible light Trevor C. Sherwood, Hai-Yun Xiao, Roshan G. Bhaskar, Eric M. Simmons, Serge Zaretsky, Martin P. Rauch, Robert R Knowles, and T. G. Murali Dhar J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Mar 2019 Downloaded from http://pubs.acs.org on March 24, 2019
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The Journal of Organic Chemistry
Decarboxylative intramolecular arene alkylation using N(acyloxy)phthalimides, an organic photocatalyst, and visible light Trevor C. Sherwood,*1 Hai-Yun Xiao,*1 Roshan G. Bhaskar,1 Eric M. Simmons,2 Serge Zaretsky,2 Martin P. Rauch,3 Robert R. Knowles,3 T. G. Murali Dhar1 1Research
and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, New Jersey 08543-4000 United States 2Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States 3Department
of Chemistry, Princeton University, Princeton, NJ, 08544, United States
Supporting Information Placeholder O
X R1
n = 0-2
O O
N
O X = C(O), CH2, NR , O, SO2
4CzIPN, TFA DMSO
X R
40 W Purple LEDs
1
n
up to 76% yield
2
ABSTRACT: An intramolecular arene alkylation reaction has been developed using the organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)phthalimides as radical precursors. Reaction conditions were optimized via high-throughput experimentation, and electron-rich and electron-deficient arenes and heteroarenes are viable reaction substrates. This reaction enables access to a diverse set of fused, partially saturated cores which are of high interest in synthetic and medicinal chemistry.
INTRODUCTION The structural complexity of new molecular entities disclosed by pharmaceutical researchers continues to increase as is evident from the literature.1 In order to enable chemists to continue to access novel scaffolds, the development of new methods for core synthesis, specifically cyclizations, are of paramount importance. Methods that enable the incorporation of sp3-hybridized carbons are of specific interest to medicinal chemists as C(sp3) incorporation can increase the threedimensionality of pharmaceutical scaffolds, which is highly desirable.2 In addition, alternate bond forming methods for the construction of partially saturated ring systems are of high interest to the chemistry community. Towards this end, we sought to develop a C(sp3)-C(sp2) cyclization reaction to give fused, partially saturated structures with good functional group tolerance. The intramolecular Friedel-Crafts reaction is a classical approach for carbon-carbon bond formation but typically requires harsh acidic conditions, is not highly functional group tolerant, and is limited to electron-rich arene substrates.3 Radical chemistry,4 on the other hand, is a wellappreciated complement to Friedel-Crafts chemistry,5 with many radical-based reactions for intramolecular arene alkylation already established.6-11 For example, alkyl halides6 have been used in conjunction with tin reagents, peroxides, or transition metal catalysts for such cyclizations, as have alkyl xanthate esters (Scheme 1a)7 under peroxide conditions. Photoredox chemistry12 has seen some use for intramolecular arene alkylation with recent examples focused on pyrrole-
containing scaffolds, alkyl halides, and transition metal photocatalysts (Scheme 1b).13 Scheme 1. Select methods for intramolecular arene alkylation a. Example of non-photoinduced, peroxide-mediated intramolecular arene alkylation O
O S R
OEt
dilauroyl peroxide
ref 7a
S
1
2
R
b. Examples of metal-mediated photoredox intramolecular arene alkylation R Br
N
Photocatalyst
N light R 4 3 Visible light - Pd catalyst, R = H (ref 13c); Ru catalyst, R = ester (ref 13a); UV light - Au, R = H (ref 13b)
R R
c. This work - visible-light photoredox decarboxylative intramolecular arene alkylation O
X R1
n = 0-2
O O
N
O 5 - formed in situ or isolated 2 X = C(O), CH2, NR , O, SO2
4CzIPN (PC1), TFA DMSO visible light
X R1
n
6
We recently disclosed an organocatalyzed, visible-light photoredox-mediated Minisci reaction using in situ prepared N(acyloxyphthalimides) (NAPs) from carboxylic acids which has demonstrated a high degree of functional group tolerance.14,15 We hypothesized that our Minisci method could be extended to
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intramolecular arene alkylation if a radical formed from reductive fragmentation of generic NAP 5 could engage a tethered arene as shown in Scheme 1c. The alkyl radical should be particularly well-suited for reaction with electron-deficient arenes in close analogy to the Minisci reaction.16 Given the requirement in Friedel-Crafts cyclizations for an electron-rich arene, our proposed reaction would be particularly attractive for use with electron-poor arenes for which Friedel-Crafts chemistry would be difficult. In contrast to typical Minisci processes, application to electron-rich arenes may be feasible, as well, due to the tethered nature of the reactive partners. While NAPs have recently seen widespread use,17 to the best of our knowledge, our work disclosed herein is the first example employing NAPs for intramolecular arene alkylation under photoredox conditions.
RESULTS AND DISCUSSION We began our studies targeting the synthesis of -tetralone (7b, Scheme 2) as the ketone moiety provides an electrondeficient arene partner and can be used as a handle for postcyclization modification. While there are examples of nonphotoredox radical cyclizations for tetralone formation using xanthates7a or an alkyl halide,6d the peroxide conditions used can lead to product degradation if the reaction is not closely monitored. Application of our mild Minisci conditions would avoid such an undesired side reaction. Scheme 2. Proof-of-concept experiments O
O
O O
photocatalyst, TFA DMSO, cooling fan
N
O
34 W blue LEDs (461 nm)
O
7a
O
Me 7c
7b
Photocatalyst PC1: 27% yield (one-pot)a Photocatalyst PC2: 44% yieldb
CF3
F
NC
CN
N
N
N
F F
Ir
III
formation of 7b, ratio of cyclized to uncyclized 7b:7c, and consumption of starting material 7a. Our HTE began with a broad screen of photocatalysts under blue light (470 nm) irradiation examining Ru and Ir complexes,18 as well as organic photocatalysts.22 As expected based on our proof-of-concept experiments, Ir complex PC2 with TFA (1.5 equiv) provided desired 7b with a favorable ratio of 7b:7c and complete consumption of 7a (entry 1). Running the reaction with 1 mol % of PC1 gave similar results (entry 2) to PC2. While a variety of Ir complexes proved effective, other organic photocatalysts and Ru complexes gave unfavorable results with a significant amount of 7a remaining unconsumed (see Table S1). Therefore, select Ir complexes as well as PC1 were chosen for further optimization. Decreasing the loading of PC1 to 0.5 mol % (entry 3) maintained reaction efficiency, although throughput with Ir complex PC2 suffered with reduced loading. Table 1. Select HTE entries optimizing the formation of -t etralone (7b)a O
O
O
O
O
visible light
O
7a
O
photocatalyst, acid additive solvent, 15-19 h, rt - 35 oC
N
Me 7c
7b
acid (equiv)
light (nm)
AP of 7ba
AP of 7aa
7b:7ca
PC2b
TFA (1.5)
470
74
0.17
88:12
2
PC1
b
TFA (1.5)
470
74
0.42
88:12
3
PC1
TFA (1.5)
470
73
0.25
87:13
4
PC1
TFA (1.5)
527
15
79
86:14
5
PC1
TFA (1.5)
white
64
14
88:12
6
c
PC1
TFA (1.5)
415
73
0.24
87:13
entry
PC
1
7
PC1
BF3•OEt2 (1.5)
470
59
21
87:13
8c
PC1
BF3•OEt2 (1.5)
415
72
0.21
86:14
9
PC1
TFA (1.0)
415
67
5.10
85:15
10
PC1
TFA (1.0)
415
61
26
93:7
11
d
PC1
TFA (10)
415
81
4.5
94:6
12d
PC3
TFA (1.0)
415
80
0.70
91:9
13
PC1
-
415
23
62
77:23
14
-
TFA (3.0)
415
